The senescent heart is particularly vulnerable to hemodynamic stress, including pressure overload and ischemia. Maturation and aging of adult cardiac myocytes occur within the context of nonmyocyte cardiac tissue and other organ systems, which modulate their function through autocrine and paracrine mechanisms. Thus, senescent cardiac myocytes are exposed to a chronic hormonal milieu, which may make it particularly susceptible during conditions of physiologic stress. Furthermore, a number of studies suggest that stress-induced protective mechanisms, in the young heart, may be absent or attenuated in the senescent myocardium and that aging myocardium exhibits an increase in apoptotic and necrotic cell loss. In the aged heart, there is a diminished induction of proto-oncogenes following hemodynamic stress, also suggesting that the remodeling capacity of the heart may be impaired. Since receptor-mediated signaling pathways modulate PKC activation, these data underscore the importance of isolating both extracardiac and intrinsic mechanisms that may be responsible for the desensitization of the senescent heart. Thus, the specific aims of this proposal are twofold: First, to address the question of whether the context (hormonal milieu) mediates stress-induced desensitization of the senescent heart and second, to address the question of whether intrinsic mechanisms (cardiac muscle) are responsible for the vulnerability of the senescent heart to ischemia.